Animal models constructed using pathogenic factors have significantly advanced drug development for Alzheimer's disease(AD).These predominantly transgenic models,mainly in mice,replicate pathological phenotypes th...Animal models constructed using pathogenic factors have significantly advanced drug development for Alzheimer's disease(AD).These predominantly transgenic models,mainly in mice,replicate pathological phenotypes through gene mutations associated with familial AD cases,thus serving as vital tools for assessing drug efficacy and for performing mechanistic studies.However,the speciesspecific differences and complex,heterogeneous nature of AD etiology pose considerable challenges for the translatability of these animal models,limiting their utility in drug development.This review offers a comprehensive analysis of widely employed rodent(mice and rats)and non-rodent models(Danio rerio(zebrafish),Drosophila melanogaster,and Caenorhabditis elegans),detailing their phenotypic features and specific research applications.This review also examines the limitations inherent in these models and introduces various strategies for expanding AD modeling across diverse species,emphasizing recent advancement in non-human primates(NHPs)as valuable models.Furthermore,potential insights from the integration of innovative technologies in AD research are discussed,while providing valuable perspectives on the future development of AD animal models.展开更多
Acetyltransferases,required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease.Protein acetylation is a common post-translational modification pivo...Acetyltransferases,required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease.Protein acetylation is a common post-translational modification pivotal to basic cellular processes.Close to 80%-90%of proteins are acetylated during translation,which is an irreversible process that affects protein structure,function,life,and localization.In this review,we have discussed the various N-acetyltransferases present in humans,their function,and how they might play a role in diseases.Furthermore,we have focused on N-acetyltransferase 9 and its role in microtubule stability.We have shed light on how N-acetyltransferase 9 and acetylation of proteins can potentially play a role in neurodegenerative diseases.We have specifically discussed the N-acetyltransferase 9-acetylation independent function and regulation of c-Jun N-terminal kinase signaling and microtubule stability during development and neurodegeneration.展开更多
Melatonin can attenuate cardiac microvascular ischemia/reperfusion injury,but it remains unclear whether melatonin can also ameliorate cerebral microvascular abnormalities.Rat models of Alzheimer’s disease were estab...Melatonin can attenuate cardiac microvascular ischemia/reperfusion injury,but it remains unclear whether melatonin can also ameliorate cerebral microvascular abnormalities.Rat models of Alzheimer’s disease were established by six intracerebroventricular injections of amyloidbeta 1–42,administered once every other day.Melatonin(30 mg/kg)was intraperitoneally administered for 13 successive days,with the first dose given 24 hours prior to the first administration of amyloid-beta 1–42.Melatonin ameliorated learning and memory impairments in the Morris water maze test,improved the morphology of microvessels in the cerebral cortex and hippocampus,increased microvessel density,alleviated pathological injuries of cerebral neurons,and decreased the expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2.These findings suggest that melatonin can improve microvessel abnormalities in the cerebral cortex and hippocampus by lowering the expression of vascular endothelial growth factor and its receptors,thereby improving the cognitive function of patients with Alzheimer’s disease.This study was approved by the Animal Care and Use Committee of Jinzhou Medical University,China(approval No.2019015)on December 6,2018.展开更多
The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intr...The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.展开更多
Dental pulp stem cells are dental pulp-derived mesenchymal stem cells that originate from the neural crest.They exhibit greater potential for the treatment of nervous system diseases than other types of stem cells bec...Dental pulp stem cells are dental pulp-derived mesenchymal stem cells that originate from the neural crest.They exhibit greater potential for the treatment of nervous system diseases than other types of stem cells because of their neurogenic differentiation capability and their ability to secrete multiple neurotrophic factors.Few studies have reported Alzheimer’s disease treatment using dental pulp stem cells.Rat models of Alzheimer’s disease were established by injecting amyloid-β1–42 into the hippocampus.Fourteen days later,5×106 dental pulp stem cells were injected into the hippocampus.Immunohistochemistry and western blot assays showed that dental pulp stem cell transplantation increased the expression of neuron-related doublecortin,NeuN,and neurofilament 200 in the hippocampus,while the expression of amyloid-βwas decreased.Moreover,cognitive and behavioral abilities were improved.These findings indicate that dental pulp stem cell transplantation in rats can improve cognitive function by regulating the secretion of neuron-related proteins,which indicates a potential therapeutic effect for Alzheimer’s disease.This study was approved by the Animal Ethics Committee of Harbin Medical University,China(approval No.KY2017-132)on February 21,2017.展开更多
BACKGROUND: Modem pharmacological studies have demonstrated that Panax notoginseng saponins (PNS) can ameliorate and protect from neuropathological impairment. Whether PNS can improve the abnormality in memory and ...BACKGROUND: Modem pharmacological studies have demonstrated that Panax notoginseng saponins (PNS) can ameliorate and protect from neuropathological impairment. Whether PNS can improve the abnormality in memory and behavior of rats with Alzheimer's disease (AD) remains unclear. OBJECTIVE: Based on a Morris water maze test, this study aimed to measure improvements of spatial learning and memory by PNS in a rat model of AD, and to compare effects with huperzine A. DESIGN: A completely randomized grouping design, controlled animal experiment. SETTING: Center of Research & Development of New Drugs, Guangxi Traditional Chinese Medical University. MATERIALS: Ninety healthy Wistar rats of both genders, 15-month-old (n =75) and 3-month-old rats as young controls (n =15), were used for this study. The study was performed in accordance with animal ethics guidelines for the use and care of animals. PNS was provided by Weihe Pharmaceutical Co., Ltd (permission No. Z53021485, Yuxi, Yunan Province, China). Morris water maze equipment was provided by the Institute of Physiology, Chinese Academy of Science. METHODS: This study was performed at the Center of Research & Development of New Drugs, Guangxi Traditional Chinese Medical University from June 2003 to April 2005. Of the included rats, 15 healthy aged rats were randomly chosen as aged controls, and the remaining 60 aged rats were randomly divided into 4 groups with 15 rats in each: model group, PNS high- and low-dose groups, and an huperzine A group. Rats in the model group and the 3 treated groups were treated with intraperitoneal infusion of 9.6 g/L D-galactose (5 mL/kg) every day for 6 weeks successively to induce a subacute aging model. During week 7, animals received 1 μ L ibotenic acid (5 g/L) bilaterally into the nucleus basalis of Meynert to create a rat model of AD. The young and old rat controls received, in parallel, a corresponding volume of saline. Two weeks later, rats in the PNS high- and low-dose groups were gavaged with 200 and 100 mg/kg PNS suspension, respectively. Huperzine A suspension (0.3 mg/kg) was used in the huperzine A group. Rats in the other 3 groups were gavaged with a corresponding volume of normal saline. In each group, administration was carried out once per day for 4 consecutive weeks. MAIN OUTCOME MEASURES: After administration, learning and memory abilities were measured by place navigation and spatial probe tests. Recording indices consisted of escape latency (time-to-platform), number of times to find the platform within 2 minutes, number of times the animal crosses the original platform location, and the percent of swimming time in each quadrant. RESULTS: Several rats died due to inflammatory reactions following brain lesion or intragastric administration; therefore, 61 rats were included in the final analysis. Results of spatial navigation test: Escape latency of rats in the model group was significantly prolonged, and number of times to find the platform within 2 minutes were significantly reduced compared with other groups (both P 〈 0.05). No significant differences in these two indices were measured among the administration groups (all P 〉 0.05). Results of spatial probe test: Times for crossing the original platform location and percent of time spent in the quadrant of original platform location were significantly less in the model group than in the other groups (P 〈 0.05). There were no significant differences in these two indices among the administration groups (P 〉 0.05). CONCLUSION: PNS can remarkably improve spatial learning and memory abilities of rats with AD. The therapeutic effect of PNS is not dose-dependent and is equivalent to the effect of huperzine A.展开更多
BACKGROUND: Central adrenergic nerve and 5-serotonergic nerve can influence central cholinergic nerve on learning and memory and make easy for study; however, ginsenoside of stem and leaf (GSL) can improve function...BACKGROUND: Central adrenergic nerve and 5-serotonergic nerve can influence central cholinergic nerve on learning and memory and make easy for study; however, ginsenoside of stem and leaf (GSL) can improve functions of central adrenergic nerve; moreover, 5-serotonergic nerve and the combination with choline can produce synergistic effect and enhance learning and memory ability so as to improve learning and memory disorder of patients with Alzheimer disease (AD). OBJECTIVE : To observe the effects of GSL combining with choline on learning and memory of AD model rats DESIGN : Randomized grouping design and controlled animal study SETIING : Department of Pharmacology, Taishan Medical College MATERIALS : The experiment was carried out in the Pharmacological Department of Medical College of Jilin University from October 1996 to January 1997. Forty healthy male Wistar rats of clean grade were randomly divided into 5 groups, including sham-injury group, model group, GSL group, choline group and combination group, with 8 rats in each group. Main medications: GSL with the volume more than 92.8% was provided by Department of Chemistry, Norman Bethune Medical College of Jilin University. Panaxatriol, the main component, was detected with thin layer scanning technique and regarded as the index of GSL quality [(55±1)%, CV= 2%, n = 5]. Choline was provided by the Third Shanghai Laboratory Factory. METHODS : 150 nmol quinolinic acid was used to damage bilateral Meynert basal nuclei of adult rats so as to establish AD models. Rats in GSL, choline and combination groups were intragastric administrated with 400 mg/kg GSL, 200 mg/kg choline (20 mL/kg), and both respectively last for 17 days starting from two days before operation. Rats in sham-injury group and model group were perfused with the same volume of distilled water once in each morning for the same days. (1) Passive avoidance step-down test: Five minutes later, rats jumped up safe platform when they were shocked with 36 V alternating current. If rats jumped down from the platform and the feet touched railings, the response was wrong. Numbers of wrong response were recorded within 3 minutes, and then the test was redone after 24 hours. (2) Morris water-maze spatial localization task: Swimming from jumping-off to platform directly was regarded as right response. Additionally, 4 successively right responses were regarded as the standard. Each rat was trained 10 times a day with 120 s per time for 3 successive days. The interval was 30 s. Three days later, numbers of right response were recorded. The training times were increased to 30 for unlearned rats. (3) Measurement of activity of choline acetylase in cerebral cortex: Rats were sacrificed at 17 days after operation to obtain cerebral cortex to measure activity of choline acetylase with radiochemistry technique. (4) Synergistic effect: It was expressed as Q value: Q value = factual incorporative effect/anticipant incorporative effect; Q ≥ 1 was regarded as synergistic effect. Anticipant incorporative effect = (EA+EB-EA·EB), EA and EB were single timing effect, respectively in GSL group and choline group. E(step-down test and Morris water maze test) = (x in model group - factual value in medicine groups)/x in model group; E (activity of choline acetylase) = (factual value in medicine groups -xin model group)/xin model group. MAIN OUTCOME MEASURES : (1) Passive avoidance step-down test and Morris water-maze spatial localization task in the study of learning and memory; (2) activity of choline acetylase. RESULTS : All 40 rats were involved in the final analysis. (1) Passive avoidance response: At learning phase on first day and retesting phase on the next day, numbers of wrong responses within 3 minutes were more in model group than sham operation group, and there was significant difference [(5.88±1.46), (2.25±0.87) times; (2.63±1.06), (0.50±0.53) times; P 〈 0.01]; numbers of wrong responses within 3 minutes were less in combination group than model group, and there was significant difference [learning phase: (1.12±0.83), (5.88±1.46) times; retesting phase: (0.38±0.74), (2.63±1.06)times, P 〈 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.07 and 1.59, respectively and it showed synergistic effect. Spatial localization task: Training times were more in model group than sham operation group, and there was significant difference [(2.9±2.5), (12.6±3.5) times; P 〈 0.01]. Training times were less in combination group than model group, and there was significant difference [(11.8±2.4), (27.9±2.5) times, P 〈 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.07 and it showed synergistic effect. (3) Activity of choline acetylase: Activity was lower in model group than sham operation group, and there was significant difference [(30.56±8.33), (61.11 ±8.33) nkat/g; P 〈 0.01]. Activity was higher in combination group than model group and there was significant difference [(50.00±8.33), (30.56±8.33) nkat/g, P 〈 0.01];moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.5 and it showed synergistic effect. CONCLUSZON: GSL in combination with choline can synergically improve the disorder of learning and memory of AD model rats. Its mechanism may be involved in enhancing the function of central cholinergic system.展开更多
Amyloid beta(Aβ)monomers aggregate to form fibrils and amyloid plaques,which are critical mechanisms in the pathogenesis of Alzheimer’s disease(AD).Given the important role of Aβ1-42 aggregation in plaque formation...Amyloid beta(Aβ)monomers aggregate to form fibrils and amyloid plaques,which are critical mechanisms in the pathogenesis of Alzheimer’s disease(AD).Given the important role of Aβ1-42 aggregation in plaque formation,leading to brain lesions and cognitive impairment,numerous studies have aimed to reduce Aβaggregation and slow AD progression.The diphenylalanine(FF)sequence is critical for amyloid aggregation,and magnetic fields can affect peptide alignment due to the diamagnetic anisotropy of aromatic rings.In this study,we examined the effects of a moderate-intensity rotating magnetic field(RMF)on Aβaggregation and AD pathogenesis.Results indicated that the RMF directly inhibited Aβamyloid fibril formation and reduced Aβ-induced cytotoxicity in neural cells in vitro.Using the AD mouse model APP/PS1,RMF restored motor abilities to healthy control levels and significantly alleviated cognitive impairments,including exploration and spatial and non-spatial memory abilities.Tissue examinations demonstrated that RMF reduced amyloid plaque accumulation,attenuated microglial activation,and reduced oxidative stress in the APP/PS1 mouse brain.These findings suggest that RMF holds considerable potential as a non-invasive,high-penetration physical approach for AD treatment.展开更多
BACKGROUND: It has been previously shown that the muscarinic (M) receptor is involved in brain arousal and selective attention, mood, and motor coordination. OBJECTIVE: To explore the effects of various intragastr...BACKGROUND: It has been previously shown that the muscarinic (M) receptor is involved in brain arousal and selective attention, mood, and motor coordination. OBJECTIVE: To explore the effects of various intragastric Daicong doses on hippocampal MI and M3 receptor gene expression in a rat model of Alzheimer's disease. DESIGN, TIME AND SETTING: A randomized cellular and molecular biology experiment, conducted at the Molecular Immunology Laboratory in Shandong between October 2006 and April 2007. MATERIALS: Fifty 22-month old Sprague Dawley rats, weighing 250-300 g were used for this experiment. Kainic acid was used to lesion the nucleus basalis to establish a rat model of Alzheimer's disease. The components of Daicong solution were as follows: ginseng, rehmannia dride rhizome, anemarrhena, and radix astragali. The solution was provided by the Affiliated Hospital to Weifang Medical College, according to preparation techniques of extracting liquid for traditional Chinese medicine (1 g crude drug/mL solution). Kainic acid was provided by Professor Xiuyan Li at Weifang Medical College. METHODS: The rats were randomly divided into 5 groups, 10 rats in each group. Four groups were used for model establishment, and the fifth group served as a normal control group. Three of the model groups were intragastrically administered 5, 10, and 20 g/kg/d Daicong solution, and an additional model group and normal control group received normal saline (10 mL/kg/d). Drugs were administered over a time period of one month. MAIN OUTCOME MEASURES: Four days after model establishment, Morris water maze was used to measure learning and memory capabilities. RT-PCR was used to detect the effect of Daicong solution on mRNA expression of M1 and M3 receptor in the hippocampus of all groups. RESULTS: Fifty rats were included in the final analysis, without any loss. M1 and M3 receptor mRNA expression was decreased in the model group, compared to the normal control group (P 〈 0.05). Upon Daicong administration (10 g/kg/d and 20 g/kg/d), M1 and M3 receptor mRNA expression significantly increased in the hippocampus, compared to the model group (P 〈 0.05). M1 and M3 mRNA expression was greatest in the 10 g/kg/d group. CONCLUSION: A 10 g/kg/d solution of Daicong can improve M1 and M3 receptor mRNA expression in the hippocampus of a rat model of Alzheimer's disease.展开更多
Studies have shown that mesenchymal stem cell-derived exosomes can enhance neural plasticity and improve cognitive impairment.The purpose of this study was to investigate the effects of mesenchymal stem cell-derived e...Studies have shown that mesenchymal stem cell-derived exosomes can enhance neural plasticity and improve cognitive impairment.The purpose of this study was to investigate the effects of mesenchymal stem cell-derived exosomes on neurogenesis and cognitive capacity in a mouse model of Alzheimer’s disease.Alzheimer’s disease mouse models were established by injection of beta amyloid 1?42 aggregates into dentate gyrus bilaterally.Morris water maze and novel object recognition tests were performed to evaluate mouse cognitive deficits at 14 and 28 days after administration.Afterwards,neurogenesis in the subventricular zone was determined by immunofluorescence using doublecortin and PSA-NCAM antibodies.Results showed that mesenchymal stem cells-derived exosomes stimulated neurogenesis in the subventricular zone and alleviated beta amyloid 1?42-induced cognitive impairment,and these effects are similar to those shown in the mesenchymal stem cells.These findings provide evidence to validate the possibility of developing cell-free therapeutic strategies for Alzheimer’s disease.All procedures and experiments were approved by Institutional Animal Care and Use Committee(CICUAL)(approval No.CICUAL 2016-011)on April 25,2016.展开更多
Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer’s disease(AD)have been made and multifarious novel therapeutic approaches have been developed,AD remains an incurable disease.E...Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer’s disease(AD)have been made and multifarious novel therapeutic approaches have been developed,AD remains an incurable disease.Evidence shows that AD neuropathology occurs decades before clinical presentation.AD is divided into three stages:preclinical stage,mild cognitive impairment(MCI),and AD dementia.In the natural world,some animals,such as non-human primates(NHPs)and canines,can develop spontaneous AD-like dementia.However,most animals do not develop AD.With the development of transgenic techniques,both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment methods.Most AD research focuses on early-onset familial AD(FAD)because FAD is associated with specific genetic mutations.However,there are no well-established late-onset sporadic AD(SAD)animal models because SAD is not directly linked to any genetic mutation,and multiple environmental factors are involved.Moreover,the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical stages.This review summarizes the common models used to study AD,from yeast to NHP models,and discusses the different applications,evaluation methods,and challenges related to AD animal models,as well as prospects for the evolution of future studies.展开更多
After gene mutation, the pcDNA3.1/APP595/596 plasmid was transfected into HEK293 cells to establish a cell model of Alzheimer's disease. The cell model was treated with donepezil or compound Danshen tablets after cul...After gene mutation, the pcDNA3.1/APP595/596 plasmid was transfected into HEK293 cells to establish a cell model of Alzheimer's disease. The cell model was treated with donepezil or compound Danshen tablets after culture for 72 hours. Reverse transcription-PCR showed that the mRNA expression of amyloid protein precursor decreased in all groups following culture for 24 hours, and that there was no significant difference in the amount of decrease between donepezil and compound Danshen tablets. Our results suggest that compound Danshen tablets can reduce expression of the mRNA for amyloid protein precursor in a transgenic cell model of Alzheimer's disease, with similar effects to donepezil.展开更多
Alzheimer’s disease(AD)is a progressive neurodegenerative disorder and the most common form of dementia worldwide.As age is the main risk factor,>97%of all AD cases are of sporadic origin,potentiated by various ri...Alzheimer’s disease(AD)is a progressive neurodegenerative disorder and the most common form of dementia worldwide.As age is the main risk factor,>97%of all AD cases are of sporadic origin,potentiated by various risk factors associated with life style and starting at an age>60 years.Only<3%of AD cases are of genetic origin caused by mutations in the amyloid precursor protein or Presenilins 1 or 2,and symptoms already start at an age<30 years.In order to study progression of AD,as well as therapeutic strategies,mouse models are state-of-the-art.So far many transgenic mouse models have been developed and used,with mutations in the APP or presenilin or combinations(3×Tg,5×Tg).However,such transgenic mouse models more likely mimic the genetic form of AD and no information can be given how sporadic forms develop.Several risk genes,such as Apolipoprotein E4 and TREM-2 enhance the risk of sporadic AD,but also many risk factors associated with life style(e.g.,diabetes,hypercholesterolemia,stress)may play a role.In this review we discuss the current situation regarding AD mouse models,and the problems to develop a sporadic mouse model of AD.展开更多
The acute effect of acupuncture on Alzheimer's disease,i.e.,on brain activation during treatment,has been reported.However,the effect of long-term acupuncture on brain activation in Alzheimer's disease is unclear.Th...The acute effect of acupuncture on Alzheimer's disease,i.e.,on brain activation during treatment,has been reported.However,the effect of long-term acupuncture on brain activation in Alzheimer's disease is unclear.Therefore,in this study,we performed long-term needling at Zusanli(ST36)or a sham point(1.5 mm lateral to ST36)in a rat Alzheimer's disease model,for 30 minutes,once per day,for 30 days.The rats underwent 18F-fluorodeoxyglucose positron emission tomography scanning.Positron emission tomography images were processed with SPM2.The brain areas activated after needling at ST36 included the left hippocampus,the left orbital cortex,the left infralimbic cortex,the left olfactory cortex,the left cerebellum and the left pons.In the sham-point group,the activated regions were similar to those in the ST36 group.However,the ST36 group showed greater activation in the cerebellum and pons than the sham-point group.These findings suggest that long-term acupuncture treatment has targeted regulatory effects on multiple brain regions in rats with Alzheimer's disease.展开更多
Alzheimer’s disease is a primary age-related neurodegenerative disorder that can result in impaired cognitive and memory functions.Although connections between changes in brain networks of Alzheimer’s disease patien...Alzheimer’s disease is a primary age-related neurodegenerative disorder that can result in impaired cognitive and memory functions.Although connections between changes in brain networks of Alzheimer’s disease patients have been established,the mechanisms that drive these alterations remain incompletely understood.This study,which was conducted in 2018 at Northeastern University in China,included data from 97 participants of the Alzheimer’s Disease Neuroimaging Initiative(ADNI)dataset covering genetics,imaging,and clinical data.All participants were divided into two groups:normal control(n=52;20 males and 32 females;mean age 73.90±4.72 years)and Alzheimer’s disease(n=45,23 males and 22 females;mean age 74.85±5.66).To uncover the wiring mechanisms that shaped changes in the topology of human brain networks of Alzheimer’s disease patients,we proposed a local naive Bayes brain network model based on graph theory.Our results showed that the proposed model provided an excellent fit to observe networks in all properties examined,including clustering coefficient,modularity,characteristic path length,network efficiency,betweenness,and degree distribution compared with empirical methods.This proposed model simulated the wiring changes in human brain networks between controls and Alzheimer’s disease patients.Our results demonstrate its utility in understanding relationships between brain tissue structure and cognitive or behavioral functions.The ADNI was performed in accordance with the Good Clinical Practice guidelines,US 21 CFR Part 50-Protection of Human Subjects,and Part 56-Institutional Review Boards(IRBs)/Research Good Clinical Practice guidelines Institutional Review Boards(IRBs)/Research Ethics Boards(REBs).展开更多
BACKGROUND: Neuronal loss, synapse mutilation, and increasing malnourished axons are pathologically related to Alzheimer's disease. Microtubule-associated protein 2 (MAP2) is of importance for neuronal, axonal, an...BACKGROUND: Neuronal loss, synapse mutilation, and increasing malnourished axons are pathologically related to Alzheimer's disease. Microtubule-associated protein 2 (MAP2) is of importance for neuronal, axonal, and dendritic generation, extension, and stabilization, as well as for the regulation of synaptic plasticity. OBJECTIVE: To investigate the antagonistic effects of natural-cerebrolysin-containing serum on beta amyloid protein 1-40 (Aβ1-40)-induced neurotoxicity from the standpoints of cell proliferation, synaptogenesis, and cytoskeleton formation (MAP2 expression). DESIGN, TIME AND SETTING: A paralleled, controlled, neural cell, and molecular biology experiment was performed at the Institute of Integrated Chinese and Western Medicine, Shenzhen Hospital, Southern Medical University between February 2006 and April 2008. MATERIALS: PC12 cells, derived from the rat central nervous system, were purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences, China. A β1-40 was provided by Sigma, USA. Natural-cerebrolysin was provided by Shenzhen Institute of Integrated Chinese and Western Medicine, China. The natural-cerebrolysin was predominantly composed of Renshen (Radix Ginseng), Tianma (Rhizoma Gastrodiae), and Yixingye (Ginkgo Leaf) in a proportion of 1:2:2. Following conventional water extraction technology, an extract (1:20) was prepared. Each gram of extract equaled 20 grams of crude drug. In a total of 12 adult male New Zealand rabbits, six underwent intragastric administration of natural-cerebrolysin extract for 1 month to prepare natural-cerebrolysin-containing serum, and the remaining six rabbits received intragastric administration of physiological saline to prepare normal blank serum. METHODS: An AIzheimer's disease in vitro model was induced in PC12 cells using Aβ1-40. The cells were incubated with varying doses of natural-cerebrolysin-containing serum (2.5%, 5%, and 10%). Normal blank serum-treated PC12 cells served as a blank control group. MAIN OUTCOME MEASURES: Through the use of inverted phase contrast microscope, cell morphology and neurite growth were observed, neurite length was measured, and the percentage of neurite-positive cells was calculated. Cell proliferation rate was determined by MTT assay, and MAP 2 expression was detected by fluorescent immunocytochemistry. RESULTS: Following Aβ1-40 treatments, some PC12 cells were apoptotic/dying, and only a few short neurites were observed. Following interventions with natural-cerebrolysin-containing serum, the PC12 cells proliferated, there was an increased number of neurites, and neurite length was enhanced. After middle- and high-dose natural-cerebrolysin treatments, the percentage of neurite-positive cells, as well as the average length of neurites, was significantly greater than the normal blank serum-treated PC12 cells (P 〈 0.05 or P 〈 0.01). Compared with the blank control group, MAP2 expression in the Aβ1-40-treated PC12 cells was significantly inhibited, and the cell proliferation rate was significantly decreased (P 〈 0.01). Following incubations with natural-cerebrolysin-containing serum, MAP2 expression and cell proliferation rate in the PC12 cells were significantly increased in a dose-dependent manner, compared with treatments with blank control serum (P 〈 0.05 or P 〈 0.01 ). CONCLUSION: Natural-cerebrolysin exhibited antagonistic effects on neurotoxicity in Aβ1-40 induced Alzheimer's disease in vitro models. These effects were likely related to cell proliferation and the upregulation of intracellular MAP2 expression.展开更多
Ca^2+ dysregulation is an early event observed in Alzheimer's disease(AD) patients preceding the presence of its clinical symptoms.Dysregulation of neuronalCa^2+ will cause synaptic loss and neuronal death,eventu...Ca^2+ dysregulation is an early event observed in Alzheimer's disease(AD) patients preceding the presence of its clinical symptoms.Dysregulation of neuronalCa^2+ will cause synaptic loss and neuronal death,eventually leading to memory impairments and cognitive decline.Treatments targetingCa^2+ signaling pathways are potential therapeutic strategies against AD.The complicated interactions make it challenging and expensive to study the underlying mechanisms as to how Ca^2+ signaling contributes to the pathogenesis of AD.Computational modeling offers new opportunities to study the signaling pathway and test proposed mechanisms.In this mini-review,we present some computational approaches that have been used to study Ca^2+ dysregulation of AD by simulating Ca^2+signaling at various levels.We also pointed out the future directions that computational modeling can be done in studying the Ca^2+ dysregulation in AD.展开更多
Alzheimer’s disease(AD)is the most common type of dementia in elderly population.With a growing aging population not only in the United States but also in the worldwide,AD constitutes an emergent public health prob...Alzheimer’s disease(AD)is the most common type of dementia in elderly population.With a growing aging population not only in the United States but also in the worldwide,AD constitutes an emergent public health problem.展开更多
Alzheimer's disease, the leading cause of dementia in the elderly, is a complex neurodegenerative disorder which leads to a progressive decline in cognitive functions. A rapid screening model is highly demanded for i...Alzheimer's disease, the leading cause of dementia in the elderly, is a complex neurodegenerative disorder which leads to a progressive decline in cognitive functions. A rapid screening model is highly demanded for identification and evaluation of novel anti-Alzheimer's disease drugs from a large numbers of compounds. Until now, numerous studies utilized zebrafish model for drug discovery. Since aluminum can induce a similar biological activity in zebrafish as in Alzheimer patients, in this study, we developed a novel animal model using 3 to 5 day post-fertilization larval zebrafish by optimizing the doses and duration of aluminum chloride exposure. Six anti-Alzheimer's disease drugs with a variety of mechanisms were tested to validate the newly developed zebrafish model. Importantly, Rivastigmine, ThT, Flurbiprofen and AM-117 could increase the value of Dyskinesia Recovery Rate by 53.4-64%, 169.4-200%, 54.5-96% and 70.9-121%, respectively. Rivastigmine, Memantine, ThT, Flurbiprofen, Rosiglitazone and AM-117 improved the value of Response Efficiency by 86.6-175.1%, 28.2-66.6%, 127.2-236.5%, 118.3-323.7%, 26.6-140.8% and 70.2-161.4%, respectively. Our results suggest that the zebrafish model developed in this study could be a useful tool for high throughput screening of potential novel anti-Alzheimer's disease leading compounds targeting acetylcholinesterase, N-methyl-D-aspartic acid receptor, γ-secretase, peroxisome proliferator-activated receptor-γand amyloid-β.展开更多
Associative memory, one of the major cognitive functions in the hippocampal CA3 region, includes auto-associative memory and hetero-associative memory. Many previous studies have shown that Alzheimer's disease (AD)...Associative memory, one of the major cognitive functions in the hippocampal CA3 region, includes auto-associative memory and hetero-associative memory. Many previous studies have shown that Alzheimer's disease (AD) can lead to loss of functional synapses in the central nervous system, and associative memory functions in patients with AD are often impaired, but few studies have addressed the effect of AD on hetero-associative memory in the hippocampal CA3 region. In this study, based on a simplified anatomical structure and synaptic connections in the hippocampal CA3 region, a three-layered Hopfield-like neural network model of hippocampal CA3 was proposed and then used to simulate associative memory functions in three circumstances: normal, synaptic deletion and synaptic compensation, according to Ruppin's synaptic deletion and compensation theory. The influences of AD on hetero-associative memory were further analyzed. The simulated results showed that the established three-layered Hopfield-like neural network model of hippocampal CA3 has both auto-associative and hetero-associative memory functions. With increasing synaptic deletion level, both associative memory functions were gradually impaired and the mean firing rates of the neurons within the network model were decreased. With gradual increasing synaptic compensation, the associative memory functions of the network were improved and the mean firing rates were increased. The simulated results suggest that the Hopfield-like neural network model can effectively simulate both associative memory functions of the hippocampal CA3 region. Synaptic deletion affects both auto-associative and hetero-associative memory functions in the hippocampal CA3 region, and can also result in memory dysfunction. To some extent, synaptic compensation measures can offset two kinds of associative memory dysfunction caused by synaptic deletion in the hippocampal CA3 area.展开更多
基金supported by the National Key Research and Development Program of China(2021YFC2500100)Major Science&Technology Program of Sichuan Province(2022ZDZX0021)+2 种基金National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(Z2024JC007)Sichuan Science and Technology Program(2024YFHZ0010,2024NSFSC1643)West China Hospital 1.3.5 Project for Disciplines of Excellence(ZYYC23016)。
文摘Animal models constructed using pathogenic factors have significantly advanced drug development for Alzheimer's disease(AD).These predominantly transgenic models,mainly in mice,replicate pathological phenotypes through gene mutations associated with familial AD cases,thus serving as vital tools for assessing drug efficacy and for performing mechanistic studies.However,the speciesspecific differences and complex,heterogeneous nature of AD etiology pose considerable challenges for the translatability of these animal models,limiting their utility in drug development.This review offers a comprehensive analysis of widely employed rodent(mice and rats)and non-rodent models(Danio rerio(zebrafish),Drosophila melanogaster,and Caenorhabditis elegans),detailing their phenotypic features and specific research applications.This review also examines the limitations inherent in these models and introduces various strategies for expanding AD modeling across diverse species,emphasizing recent advancement in non-human primates(NHPs)as valuable models.Furthermore,potential insights from the integration of innovative technologies in AD research are discussed,while providing valuable perspectives on the future development of AD animal models.
基金supported by 1RO1EY032959-01 and RO1 supplement from NIH,Schuellein Chair Endowment Fund and STEM Catalyst Grant from the University of Dayton(to AS).
文摘Acetyltransferases,required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease.Protein acetylation is a common post-translational modification pivotal to basic cellular processes.Close to 80%-90%of proteins are acetylated during translation,which is an irreversible process that affects protein structure,function,life,and localization.In this review,we have discussed the various N-acetyltransferases present in humans,their function,and how they might play a role in diseases.Furthermore,we have focused on N-acetyltransferase 9 and its role in microtubule stability.We have shed light on how N-acetyltransferase 9 and acetylation of proteins can potentially play a role in neurodegenerative diseases.We have specifically discussed the N-acetyltransferase 9-acetylation independent function and regulation of c-Jun N-terminal kinase signaling and microtubule stability during development and neurodegeneration.
基金This study was supported by the National Natural Science Foundation of China,No.81370462(to JB)the Climbing Scholars Support Plan of Liaoning Province of China(to JB)+1 种基金the Principal’s Fund of Liaoning Medical University of China,No.20140107(to PW)the Natural Science Foundation of Liaoning Province of China,No.20180551185(to PW).
文摘Melatonin can attenuate cardiac microvascular ischemia/reperfusion injury,but it remains unclear whether melatonin can also ameliorate cerebral microvascular abnormalities.Rat models of Alzheimer’s disease were established by six intracerebroventricular injections of amyloidbeta 1–42,administered once every other day.Melatonin(30 mg/kg)was intraperitoneally administered for 13 successive days,with the first dose given 24 hours prior to the first administration of amyloid-beta 1–42.Melatonin ameliorated learning and memory impairments in the Morris water maze test,improved the morphology of microvessels in the cerebral cortex and hippocampus,increased microvessel density,alleviated pathological injuries of cerebral neurons,and decreased the expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2.These findings suggest that melatonin can improve microvessel abnormalities in the cerebral cortex and hippocampus by lowering the expression of vascular endothelial growth factor and its receptors,thereby improving the cognitive function of patients with Alzheimer’s disease.This study was approved by the Animal Care and Use Committee of Jinzhou Medical University,China(approval No.2019015)on December 6,2018.
文摘The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.
基金This study was supported by Yu Weihan Fund for Distinguished Young Scholars of Harbin Medical University of China,No.002000013(to XMZ).
文摘Dental pulp stem cells are dental pulp-derived mesenchymal stem cells that originate from the neural crest.They exhibit greater potential for the treatment of nervous system diseases than other types of stem cells because of their neurogenic differentiation capability and their ability to secrete multiple neurotrophic factors.Few studies have reported Alzheimer’s disease treatment using dental pulp stem cells.Rat models of Alzheimer’s disease were established by injecting amyloid-β1–42 into the hippocampus.Fourteen days later,5×106 dental pulp stem cells were injected into the hippocampus.Immunohistochemistry and western blot assays showed that dental pulp stem cell transplantation increased the expression of neuron-related doublecortin,NeuN,and neurofilament 200 in the hippocampus,while the expression of amyloid-βwas decreased.Moreover,cognitive and behavioral abilities were improved.These findings indicate that dental pulp stem cell transplantation in rats can improve cognitive function by regulating the secretion of neuron-related proteins,which indicates a potential therapeutic effect for Alzheimer’s disease.This study was approved by the Animal Ethics Committee of Harbin Medical University,China(approval No.KY2017-132)on February 21,2017.
基金Supported by: the National Natural Science Foundation of China, No. 30560189the Grant from Innovation Groupfor Developing Chinese HerbsNew Drugsamong University Talents in Guangxi
文摘BACKGROUND: Modem pharmacological studies have demonstrated that Panax notoginseng saponins (PNS) can ameliorate and protect from neuropathological impairment. Whether PNS can improve the abnormality in memory and behavior of rats with Alzheimer's disease (AD) remains unclear. OBJECTIVE: Based on a Morris water maze test, this study aimed to measure improvements of spatial learning and memory by PNS in a rat model of AD, and to compare effects with huperzine A. DESIGN: A completely randomized grouping design, controlled animal experiment. SETTING: Center of Research & Development of New Drugs, Guangxi Traditional Chinese Medical University. MATERIALS: Ninety healthy Wistar rats of both genders, 15-month-old (n =75) and 3-month-old rats as young controls (n =15), were used for this study. The study was performed in accordance with animal ethics guidelines for the use and care of animals. PNS was provided by Weihe Pharmaceutical Co., Ltd (permission No. Z53021485, Yuxi, Yunan Province, China). Morris water maze equipment was provided by the Institute of Physiology, Chinese Academy of Science. METHODS: This study was performed at the Center of Research & Development of New Drugs, Guangxi Traditional Chinese Medical University from June 2003 to April 2005. Of the included rats, 15 healthy aged rats were randomly chosen as aged controls, and the remaining 60 aged rats were randomly divided into 4 groups with 15 rats in each: model group, PNS high- and low-dose groups, and an huperzine A group. Rats in the model group and the 3 treated groups were treated with intraperitoneal infusion of 9.6 g/L D-galactose (5 mL/kg) every day for 6 weeks successively to induce a subacute aging model. During week 7, animals received 1 μ L ibotenic acid (5 g/L) bilaterally into the nucleus basalis of Meynert to create a rat model of AD. The young and old rat controls received, in parallel, a corresponding volume of saline. Two weeks later, rats in the PNS high- and low-dose groups were gavaged with 200 and 100 mg/kg PNS suspension, respectively. Huperzine A suspension (0.3 mg/kg) was used in the huperzine A group. Rats in the other 3 groups were gavaged with a corresponding volume of normal saline. In each group, administration was carried out once per day for 4 consecutive weeks. MAIN OUTCOME MEASURES: After administration, learning and memory abilities were measured by place navigation and spatial probe tests. Recording indices consisted of escape latency (time-to-platform), number of times to find the platform within 2 minutes, number of times the animal crosses the original platform location, and the percent of swimming time in each quadrant. RESULTS: Several rats died due to inflammatory reactions following brain lesion or intragastric administration; therefore, 61 rats were included in the final analysis. Results of spatial navigation test: Escape latency of rats in the model group was significantly prolonged, and number of times to find the platform within 2 minutes were significantly reduced compared with other groups (both P 〈 0.05). No significant differences in these two indices were measured among the administration groups (all P 〉 0.05). Results of spatial probe test: Times for crossing the original platform location and percent of time spent in the quadrant of original platform location were significantly less in the model group than in the other groups (P 〈 0.05). There were no significant differences in these two indices among the administration groups (P 〉 0.05). CONCLUSION: PNS can remarkably improve spatial learning and memory abilities of rats with AD. The therapeutic effect of PNS is not dose-dependent and is equivalent to the effect of huperzine A.
文摘BACKGROUND: Central adrenergic nerve and 5-serotonergic nerve can influence central cholinergic nerve on learning and memory and make easy for study; however, ginsenoside of stem and leaf (GSL) can improve functions of central adrenergic nerve; moreover, 5-serotonergic nerve and the combination with choline can produce synergistic effect and enhance learning and memory ability so as to improve learning and memory disorder of patients with Alzheimer disease (AD). OBJECTIVE : To observe the effects of GSL combining with choline on learning and memory of AD model rats DESIGN : Randomized grouping design and controlled animal study SETIING : Department of Pharmacology, Taishan Medical College MATERIALS : The experiment was carried out in the Pharmacological Department of Medical College of Jilin University from October 1996 to January 1997. Forty healthy male Wistar rats of clean grade were randomly divided into 5 groups, including sham-injury group, model group, GSL group, choline group and combination group, with 8 rats in each group. Main medications: GSL with the volume more than 92.8% was provided by Department of Chemistry, Norman Bethune Medical College of Jilin University. Panaxatriol, the main component, was detected with thin layer scanning technique and regarded as the index of GSL quality [(55±1)%, CV= 2%, n = 5]. Choline was provided by the Third Shanghai Laboratory Factory. METHODS : 150 nmol quinolinic acid was used to damage bilateral Meynert basal nuclei of adult rats so as to establish AD models. Rats in GSL, choline and combination groups were intragastric administrated with 400 mg/kg GSL, 200 mg/kg choline (20 mL/kg), and both respectively last for 17 days starting from two days before operation. Rats in sham-injury group and model group were perfused with the same volume of distilled water once in each morning for the same days. (1) Passive avoidance step-down test: Five minutes later, rats jumped up safe platform when they were shocked with 36 V alternating current. If rats jumped down from the platform and the feet touched railings, the response was wrong. Numbers of wrong response were recorded within 3 minutes, and then the test was redone after 24 hours. (2) Morris water-maze spatial localization task: Swimming from jumping-off to platform directly was regarded as right response. Additionally, 4 successively right responses were regarded as the standard. Each rat was trained 10 times a day with 120 s per time for 3 successive days. The interval was 30 s. Three days later, numbers of right response were recorded. The training times were increased to 30 for unlearned rats. (3) Measurement of activity of choline acetylase in cerebral cortex: Rats were sacrificed at 17 days after operation to obtain cerebral cortex to measure activity of choline acetylase with radiochemistry technique. (4) Synergistic effect: It was expressed as Q value: Q value = factual incorporative effect/anticipant incorporative effect; Q ≥ 1 was regarded as synergistic effect. Anticipant incorporative effect = (EA+EB-EA·EB), EA and EB were single timing effect, respectively in GSL group and choline group. E(step-down test and Morris water maze test) = (x in model group - factual value in medicine groups)/x in model group; E (activity of choline acetylase) = (factual value in medicine groups -xin model group)/xin model group. MAIN OUTCOME MEASURES : (1) Passive avoidance step-down test and Morris water-maze spatial localization task in the study of learning and memory; (2) activity of choline acetylase. RESULTS : All 40 rats were involved in the final analysis. (1) Passive avoidance response: At learning phase on first day and retesting phase on the next day, numbers of wrong responses within 3 minutes were more in model group than sham operation group, and there was significant difference [(5.88±1.46), (2.25±0.87) times; (2.63±1.06), (0.50±0.53) times; P 〈 0.01]; numbers of wrong responses within 3 minutes were less in combination group than model group, and there was significant difference [learning phase: (1.12±0.83), (5.88±1.46) times; retesting phase: (0.38±0.74), (2.63±1.06)times, P 〈 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.07 and 1.59, respectively and it showed synergistic effect. Spatial localization task: Training times were more in model group than sham operation group, and there was significant difference [(2.9±2.5), (12.6±3.5) times; P 〈 0.01]. Training times were less in combination group than model group, and there was significant difference [(11.8±2.4), (27.9±2.5) times, P 〈 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.07 and it showed synergistic effect. (3) Activity of choline acetylase: Activity was lower in model group than sham operation group, and there was significant difference [(30.56±8.33), (61.11 ±8.33) nkat/g; P 〈 0.01]. Activity was higher in combination group than model group and there was significant difference [(50.00±8.33), (30.56±8.33) nkat/g, P 〈 0.01];moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.5 and it showed synergistic effect. CONCLUSZON: GSL in combination with choline can synergically improve the disorder of learning and memory of AD model rats. Its mechanism may be involved in enhancing the function of central cholinergic system.
基金National Key R&D Program of China(2023YFB3507004)National Natural Science Foundation of China(U21A20148)+2 种基金International Partnership Program of Chinese Academy of Sciences(116134KYSB20210052)Heye Health Technology Chong Ming Project(HYCMP2021010)CASHIPS Director’s Fund(BJPY2021A06)。
文摘Amyloid beta(Aβ)monomers aggregate to form fibrils and amyloid plaques,which are critical mechanisms in the pathogenesis of Alzheimer’s disease(AD).Given the important role of Aβ1-42 aggregation in plaque formation,leading to brain lesions and cognitive impairment,numerous studies have aimed to reduce Aβaggregation and slow AD progression.The diphenylalanine(FF)sequence is critical for amyloid aggregation,and magnetic fields can affect peptide alignment due to the diamagnetic anisotropy of aromatic rings.In this study,we examined the effects of a moderate-intensity rotating magnetic field(RMF)on Aβaggregation and AD pathogenesis.Results indicated that the RMF directly inhibited Aβamyloid fibril formation and reduced Aβ-induced cytotoxicity in neural cells in vitro.Using the AD mouse model APP/PS1,RMF restored motor abilities to healthy control levels and significantly alleviated cognitive impairments,including exploration and spatial and non-spatial memory abilities.Tissue examinations demonstrated that RMF reduced amyloid plaque accumulation,attenuated microglial activation,and reduced oxidative stress in the APP/PS1 mouse brain.These findings suggest that RMF holds considerable potential as a non-invasive,high-penetration physical approach for AD treatment.
基金the grant from Shandong Administration Bureau of Traditional Chinese Medicine, No.2001-2-75
文摘BACKGROUND: It has been previously shown that the muscarinic (M) receptor is involved in brain arousal and selective attention, mood, and motor coordination. OBJECTIVE: To explore the effects of various intragastric Daicong doses on hippocampal MI and M3 receptor gene expression in a rat model of Alzheimer's disease. DESIGN, TIME AND SETTING: A randomized cellular and molecular biology experiment, conducted at the Molecular Immunology Laboratory in Shandong between October 2006 and April 2007. MATERIALS: Fifty 22-month old Sprague Dawley rats, weighing 250-300 g were used for this experiment. Kainic acid was used to lesion the nucleus basalis to establish a rat model of Alzheimer's disease. The components of Daicong solution were as follows: ginseng, rehmannia dride rhizome, anemarrhena, and radix astragali. The solution was provided by the Affiliated Hospital to Weifang Medical College, according to preparation techniques of extracting liquid for traditional Chinese medicine (1 g crude drug/mL solution). Kainic acid was provided by Professor Xiuyan Li at Weifang Medical College. METHODS: The rats were randomly divided into 5 groups, 10 rats in each group. Four groups were used for model establishment, and the fifth group served as a normal control group. Three of the model groups were intragastrically administered 5, 10, and 20 g/kg/d Daicong solution, and an additional model group and normal control group received normal saline (10 mL/kg/d). Drugs were administered over a time period of one month. MAIN OUTCOME MEASURES: Four days after model establishment, Morris water maze was used to measure learning and memory capabilities. RT-PCR was used to detect the effect of Daicong solution on mRNA expression of M1 and M3 receptor in the hippocampus of all groups. RESULTS: Fifty rats were included in the final analysis, without any loss. M1 and M3 receptor mRNA expression was decreased in the model group, compared to the normal control group (P 〈 0.05). Upon Daicong administration (10 g/kg/d and 20 g/kg/d), M1 and M3 receptor mRNA expression significantly increased in the hippocampus, compared to the model group (P 〈 0.05). M1 and M3 mRNA expression was greatest in the 10 g/kg/d group. CONCLUSION: A 10 g/kg/d solution of Daicong can improve M1 and M3 receptor mRNA expression in the hippocampus of a rat model of Alzheimer's disease.
基金sponsored by CONACYT scholarship#487713Fondo Mixto de Ciencia y Tecnología del Estado de Jalisco grant JAL-2014-0-250508
文摘Studies have shown that mesenchymal stem cell-derived exosomes can enhance neural plasticity and improve cognitive impairment.The purpose of this study was to investigate the effects of mesenchymal stem cell-derived exosomes on neurogenesis and cognitive capacity in a mouse model of Alzheimer’s disease.Alzheimer’s disease mouse models were established by injection of beta amyloid 1?42 aggregates into dentate gyrus bilaterally.Morris water maze and novel object recognition tests were performed to evaluate mouse cognitive deficits at 14 and 28 days after administration.Afterwards,neurogenesis in the subventricular zone was determined by immunofluorescence using doublecortin and PSA-NCAM antibodies.Results showed that mesenchymal stem cells-derived exosomes stimulated neurogenesis in the subventricular zone and alleviated beta amyloid 1?42-induced cognitive impairment,and these effects are similar to those shown in the mesenchymal stem cells.These findings provide evidence to validate the possibility of developing cell-free therapeutic strategies for Alzheimer’s disease.All procedures and experiments were approved by Institutional Animal Care and Use Committee(CICUAL)(approval No.CICUAL 2016-011)on April 25,2016.
基金supported by the National Science and Technology Innovation 2030-Major Program of“Brain Science and Brain-Like Research”(2022ZD0211800)National Natural Science Foundation of China(NSFC)General Research Grants(81971679,32020103007,32088101,21727806)+1 种基金Ministry of Science and Technology(2018YFA0507600,2017YFA0503600)Qidong-PKU SLS Innovation Fund(2016000663,2017000246)。
文摘Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer’s disease(AD)have been made and multifarious novel therapeutic approaches have been developed,AD remains an incurable disease.Evidence shows that AD neuropathology occurs decades before clinical presentation.AD is divided into three stages:preclinical stage,mild cognitive impairment(MCI),and AD dementia.In the natural world,some animals,such as non-human primates(NHPs)and canines,can develop spontaneous AD-like dementia.However,most animals do not develop AD.With the development of transgenic techniques,both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment methods.Most AD research focuses on early-onset familial AD(FAD)because FAD is associated with specific genetic mutations.However,there are no well-established late-onset sporadic AD(SAD)animal models because SAD is not directly linked to any genetic mutation,and multiple environmental factors are involved.Moreover,the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical stages.This review summarizes the common models used to study AD,from yeast to NHP models,and discusses the different applications,evaluation methods,and challenges related to AD animal models,as well as prospects for the evolution of future studies.
基金supported by the Bureau of Traditional Chinese Medicine of Guangdong Province, No. 2010463the National Science and Technology"12~(th) Five-years"Major Special-purpose Foundation,No.2011ZX09201-201-01
文摘After gene mutation, the pcDNA3.1/APP595/596 plasmid was transfected into HEK293 cells to establish a cell model of Alzheimer's disease. The cell model was treated with donepezil or compound Danshen tablets after culture for 72 hours. Reverse transcription-PCR showed that the mRNA expression of amyloid protein precursor decreased in all groups following culture for 24 hours, and that there was no significant difference in the amount of decrease between donepezil and compound Danshen tablets. Our results suggest that compound Danshen tablets can reduce expression of the mRNA for amyloid protein precursor in a transgenic cell model of Alzheimer's disease, with similar effects to donepezil.
基金supported by the Austrian Science Funds(P24734-B24)
文摘Alzheimer’s disease(AD)is a progressive neurodegenerative disorder and the most common form of dementia worldwide.As age is the main risk factor,>97%of all AD cases are of sporadic origin,potentiated by various risk factors associated with life style and starting at an age>60 years.Only<3%of AD cases are of genetic origin caused by mutations in the amyloid precursor protein or Presenilins 1 or 2,and symptoms already start at an age<30 years.In order to study progression of AD,as well as therapeutic strategies,mouse models are state-of-the-art.So far many transgenic mouse models have been developed and used,with mutations in the APP or presenilin or combinations(3×Tg,5×Tg).However,such transgenic mouse models more likely mimic the genetic form of AD and no information can be given how sporadic forms develop.Several risk genes,such as Apolipoprotein E4 and TREM-2 enhance the risk of sporadic AD,but also many risk factors associated with life style(e.g.,diabetes,hypercholesterolemia,stress)may play a role.In this review we discuss the current situation regarding AD mouse models,and the problems to develop a sporadic mouse model of AD.
基金supported by the National Basic Research Program of China(973 Program),No.2006CB504505,2012CB518504the National Natural Science Foundation of China,No.90709027+1 种基金the Student's Platform for Innovation and Entrepreneurship Training Program of Southern Medical University of China,No.201512121165the Doctoral Foundation of Guangdong Medical University of China,No.2XB13058
文摘The acute effect of acupuncture on Alzheimer's disease,i.e.,on brain activation during treatment,has been reported.However,the effect of long-term acupuncture on brain activation in Alzheimer's disease is unclear.Therefore,in this study,we performed long-term needling at Zusanli(ST36)or a sham point(1.5 mm lateral to ST36)in a rat Alzheimer's disease model,for 30 minutes,once per day,for 30 days.The rats underwent 18F-fluorodeoxyglucose positron emission tomography scanning.Positron emission tomography images were processed with SPM2.The brain areas activated after needling at ST36 included the left hippocampus,the left orbital cortex,the left infralimbic cortex,the left olfactory cortex,the left cerebellum and the left pons.In the sham-point group,the activated regions were similar to those in the ST36 group.However,the ST36 group showed greater activation in the cerebellum and pons than the sham-point group.These findings suggest that long-term acupuncture treatment has targeted regulatory effects on multiple brain regions in rats with Alzheimer's disease.
基金Fundamental Research Funds for the Central Universities in China,No.N161608001 and No.N171903002
文摘Alzheimer’s disease is a primary age-related neurodegenerative disorder that can result in impaired cognitive and memory functions.Although connections between changes in brain networks of Alzheimer’s disease patients have been established,the mechanisms that drive these alterations remain incompletely understood.This study,which was conducted in 2018 at Northeastern University in China,included data from 97 participants of the Alzheimer’s Disease Neuroimaging Initiative(ADNI)dataset covering genetics,imaging,and clinical data.All participants were divided into two groups:normal control(n=52;20 males and 32 females;mean age 73.90±4.72 years)and Alzheimer’s disease(n=45,23 males and 22 females;mean age 74.85±5.66).To uncover the wiring mechanisms that shaped changes in the topology of human brain networks of Alzheimer’s disease patients,we proposed a local naive Bayes brain network model based on graph theory.Our results showed that the proposed model provided an excellent fit to observe networks in all properties examined,including clustering coefficient,modularity,characteristic path length,network efficiency,betweenness,and degree distribution compared with empirical methods.This proposed model simulated the wiring changes in human brain networks between controls and Alzheimer’s disease patients.Our results demonstrate its utility in understanding relationships between brain tissue structure and cognitive or behavioral functions.The ADNI was performed in accordance with the Good Clinical Practice guidelines,US 21 CFR Part 50-Protection of Human Subjects,and Part 56-Institutional Review Boards(IRBs)/Research Good Clinical Practice guidelines Institutional Review Boards(IRBs)/Research Ethics Boards(REBs).
基金Supported by:Scientific and Technological Foundation of the National Administration of Traditional Chinese Medicine of China,No.02-03LP41the Scientific and Technological Key Project of Guangdong Province,No. 2006B35630007
文摘BACKGROUND: Neuronal loss, synapse mutilation, and increasing malnourished axons are pathologically related to Alzheimer's disease. Microtubule-associated protein 2 (MAP2) is of importance for neuronal, axonal, and dendritic generation, extension, and stabilization, as well as for the regulation of synaptic plasticity. OBJECTIVE: To investigate the antagonistic effects of natural-cerebrolysin-containing serum on beta amyloid protein 1-40 (Aβ1-40)-induced neurotoxicity from the standpoints of cell proliferation, synaptogenesis, and cytoskeleton formation (MAP2 expression). DESIGN, TIME AND SETTING: A paralleled, controlled, neural cell, and molecular biology experiment was performed at the Institute of Integrated Chinese and Western Medicine, Shenzhen Hospital, Southern Medical University between February 2006 and April 2008. MATERIALS: PC12 cells, derived from the rat central nervous system, were purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences, China. A β1-40 was provided by Sigma, USA. Natural-cerebrolysin was provided by Shenzhen Institute of Integrated Chinese and Western Medicine, China. The natural-cerebrolysin was predominantly composed of Renshen (Radix Ginseng), Tianma (Rhizoma Gastrodiae), and Yixingye (Ginkgo Leaf) in a proportion of 1:2:2. Following conventional water extraction technology, an extract (1:20) was prepared. Each gram of extract equaled 20 grams of crude drug. In a total of 12 adult male New Zealand rabbits, six underwent intragastric administration of natural-cerebrolysin extract for 1 month to prepare natural-cerebrolysin-containing serum, and the remaining six rabbits received intragastric administration of physiological saline to prepare normal blank serum. METHODS: An AIzheimer's disease in vitro model was induced in PC12 cells using Aβ1-40. The cells were incubated with varying doses of natural-cerebrolysin-containing serum (2.5%, 5%, and 10%). Normal blank serum-treated PC12 cells served as a blank control group. MAIN OUTCOME MEASURES: Through the use of inverted phase contrast microscope, cell morphology and neurite growth were observed, neurite length was measured, and the percentage of neurite-positive cells was calculated. Cell proliferation rate was determined by MTT assay, and MAP 2 expression was detected by fluorescent immunocytochemistry. RESULTS: Following Aβ1-40 treatments, some PC12 cells were apoptotic/dying, and only a few short neurites were observed. Following interventions with natural-cerebrolysin-containing serum, the PC12 cells proliferated, there was an increased number of neurites, and neurite length was enhanced. After middle- and high-dose natural-cerebrolysin treatments, the percentage of neurite-positive cells, as well as the average length of neurites, was significantly greater than the normal blank serum-treated PC12 cells (P 〈 0.05 or P 〈 0.01). Compared with the blank control group, MAP2 expression in the Aβ1-40-treated PC12 cells was significantly inhibited, and the cell proliferation rate was significantly decreased (P 〈 0.01). Following incubations with natural-cerebrolysin-containing serum, MAP2 expression and cell proliferation rate in the PC12 cells were significantly increased in a dose-dependent manner, compared with treatments with blank control serum (P 〈 0.05 or P 〈 0.01 ). CONCLUSION: Natural-cerebrolysin exhibited antagonistic effects on neurotoxicity in Aβ1-40 induced Alzheimer's disease in vitro models. These effects were likely related to cell proliferation and the upregulation of intracellular MAP2 expression.
文摘Ca^2+ dysregulation is an early event observed in Alzheimer's disease(AD) patients preceding the presence of its clinical symptoms.Dysregulation of neuronalCa^2+ will cause synaptic loss and neuronal death,eventually leading to memory impairments and cognitive decline.Treatments targetingCa^2+ signaling pathways are potential therapeutic strategies against AD.The complicated interactions make it challenging and expensive to study the underlying mechanisms as to how Ca^2+ signaling contributes to the pathogenesis of AD.Computational modeling offers new opportunities to study the signaling pathway and test proposed mechanisms.In this mini-review,we present some computational approaches that have been used to study Ca^2+ dysregulation of AD by simulating Ca^2+signaling at various levels.We also pointed out the future directions that computational modeling can be done in studying the Ca^2+ dysregulation in AD.
基金supported by the Brazilian funding agencies:CNPq(Conselho Nacional de Desenvolvimento Científico e Tecnológico)CAPES(Coordenacao de Aperfeicoamento de Pessoal de Nível Superior)-No:5614112Student Agreement Program for post graduation–PEC-PG.
文摘Alzheimer’s disease(AD)is the most common type of dementia in elderly population.With a growing aging population not only in the United States but also in the worldwide,AD constitutes an emergent public health problem.
基金Acknowledgments The authors thank the National Natural Science Foundation of China (81302646), Natural Science Foundation of Zhejiang Province (LQ13H300002), Science Technology Department of Zhejiang Province (2015F50015) and Health and Family Planning commission of Zhejiang Province (XKQ-010-001 and 2013KYB070) for financial support.
文摘Alzheimer's disease, the leading cause of dementia in the elderly, is a complex neurodegenerative disorder which leads to a progressive decline in cognitive functions. A rapid screening model is highly demanded for identification and evaluation of novel anti-Alzheimer's disease drugs from a large numbers of compounds. Until now, numerous studies utilized zebrafish model for drug discovery. Since aluminum can induce a similar biological activity in zebrafish as in Alzheimer patients, in this study, we developed a novel animal model using 3 to 5 day post-fertilization larval zebrafish by optimizing the doses and duration of aluminum chloride exposure. Six anti-Alzheimer's disease drugs with a variety of mechanisms were tested to validate the newly developed zebrafish model. Importantly, Rivastigmine, ThT, Flurbiprofen and AM-117 could increase the value of Dyskinesia Recovery Rate by 53.4-64%, 169.4-200%, 54.5-96% and 70.9-121%, respectively. Rivastigmine, Memantine, ThT, Flurbiprofen, Rosiglitazone and AM-117 improved the value of Response Efficiency by 86.6-175.1%, 28.2-66.6%, 127.2-236.5%, 118.3-323.7%, 26.6-140.8% and 70.2-161.4%, respectively. Our results suggest that the zebrafish model developed in this study could be a useful tool for high throughput screening of potential novel anti-Alzheimer's disease leading compounds targeting acetylcholinesterase, N-methyl-D-aspartic acid receptor, γ-secretase, peroxisome proliferator-activated receptor-γand amyloid-β.
基金the National Natural Science Foundation of China,No.30870649the Natural Science Foundation of Tianjin,No.08JCYBJC03300
文摘Associative memory, one of the major cognitive functions in the hippocampal CA3 region, includes auto-associative memory and hetero-associative memory. Many previous studies have shown that Alzheimer's disease (AD) can lead to loss of functional synapses in the central nervous system, and associative memory functions in patients with AD are often impaired, but few studies have addressed the effect of AD on hetero-associative memory in the hippocampal CA3 region. In this study, based on a simplified anatomical structure and synaptic connections in the hippocampal CA3 region, a three-layered Hopfield-like neural network model of hippocampal CA3 was proposed and then used to simulate associative memory functions in three circumstances: normal, synaptic deletion and synaptic compensation, according to Ruppin's synaptic deletion and compensation theory. The influences of AD on hetero-associative memory were further analyzed. The simulated results showed that the established three-layered Hopfield-like neural network model of hippocampal CA3 has both auto-associative and hetero-associative memory functions. With increasing synaptic deletion level, both associative memory functions were gradually impaired and the mean firing rates of the neurons within the network model were decreased. With gradual increasing synaptic compensation, the associative memory functions of the network were improved and the mean firing rates were increased. The simulated results suggest that the Hopfield-like neural network model can effectively simulate both associative memory functions of the hippocampal CA3 region. Synaptic deletion affects both auto-associative and hetero-associative memory functions in the hippocampal CA3 region, and can also result in memory dysfunction. To some extent, synaptic compensation measures can offset two kinds of associative memory dysfunction caused by synaptic deletion in the hippocampal CA3 area.